HEИндивидуална стипендия2024–2026

MECHANOGUT · Probing the role of mechanosensory pathways in regulating intestinal stem cell activity and gut homeostasis

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2024-02-01 → 2026-01-31
Финансиране от ЕС: 230 774 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Механичните сили в червата, като разтягането на тъканите, регулират дейността на стволовите клетки при плодовите мухи. Разбирането на тези процеси помага да се разбере как се поддържа здравето на червната стена и какво се случва при патологичното ѝ разрастване.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Probing the role of mechanosensory pathways in regulating intestinal stem cell activity and gut homeostasis

The intestinal epithelium maintains remarkable resilience against diverse environmental and physiological challenges through the adaptive proliferation and turnover of intestinal stem cells (ISCs). This dynamic renewal is tightly regulated to preserve gut barrier integrity, as dysregulated ISC activity can lead to pathological hyperplasia. Although extensive work has identified numerous biochemical factors, autocrine, paracrine, and juxtacrine, that govern ISC homeostasis, a key unresolved question is how tissue-scale mechanical forces are sensed and transduced into biochemical signals to maintain ISC-niche equilibrium. The gut is continuously exposed to stretch, strain, and other biomechanical stresses, and accumulating evidence suggests that mechanical cues are central regulators of adult stem cell behavior. To dissect these mechanisms, this project leverages the adult Drosophila melanogaster midgut, a powerful and tractable model with a pseudostratified epithelial organization and stem cell architecture strikingly similar to the mammalian intestine. As a foundation for this work, an unbiased RNAi-based genetic screen targeting niche-expressed receptors was conducted under conditions of gut challenge using Erwinia carotovora carotovora infection. Survival assays revealed a significant enrichment of receptors involved in mechanotransductive signaling pathways, components essential for maintaining epithelial integrity during stress. Building on these preliminary findings, this project aims to uncover how mechanosensory inputs regulate ISC behavior and preserve midgut homeostasis. By integrating genetic, biomechanical, and imaging approaches, the work will elucidate fundamental principles by which mechanical forces interface with stem cell regulatory networks. These insights will advance our understanding of epithelial resilience and may reveal conserved mechanisms relevant to mammalian gut health and disease.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

In adult organisms, gut barrier function is maintained by adapting the proliferation and turnover of resident intestinal stem cells (ISCs) to environmental cues. In recent years, an immense effort in the field has successfully identified many short and long-range signals involved in ISC-driven adaptive growth responses. However, it is becoming increasingly evident that biomechanical cues, such as shear stress, compressions, swellings, and tissue-scale tension, also play a key role in regulating SC activity in adult tissues. Hence, the adult gut is constantly exposed to mechanical stress and must adapt accordingly to the stretch and strain. Despite the undisputed impact that mechanical forces have on adult organ physiology, very little is known about the molecular signals involved. Using Drosophila as a model, we performed a genetic screen for ISC niche receptors coupling environmental cues with ISC-dependent adaptive growth and identified several receptors belonging to mechanotransduction pathways as indispensable for preserving gut barrier function. Mechanical forces can be either of tissue intrinsic origin, such as forces emanating from cell division and cell death, or of external origins, such as those originating from extracellular matrix remodeling, mechanical coupling to neighboring tissues, and food and fluid flow. Recent studies in developing embryos and during tissue morphogenesis show that cells can sense mechanical forces through mechanotransducer proteins, and are used as cues to regulate gene expression patterns, cell fate specifications, cell packing, and proliferation. An insight into mechanosensation in regulating ISC niche homeostasis in mature organs is still lacking and given my scientific background in biophysics and mechanobiology, this study aims to understand the role of mechanosensory inputs in maintaining the ISC niche using the Drosophila adult gut as a model system.

Оригинален текст от CORDIS (на английски).

Участници

KOBENHAVNS UNIVERSITET · KOBENHAVNКоординаторДания